Parkin Mutation Affects Clock Gene-Dependent Energy Metabolism

Pacelli, Consiglia; Rotundo, Giovannina; Lecce, Lucia; Menga, Marta; Bidollari, Eris; Scrima, Rosella; Cela, Olga; Piccoli, Cláudia; Cocco, Tiziana; Vescovi, Angelo L.; Mazzoccoli, Gianluigi; Rosati, Jessica; Capitanio, Nazzareno

doi:10.3390/ijms20112772

Cited by 32 publications

(32 citation statements)

References 82 publications

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“…For example, the PRKN mutation may influence crosstalk between the TTFL and mitochondrial bioenergetic pathways. Fibroblasts taken from two genetic PD patients exhibited dampened oscillations in bioenergetic activities, reduced rates of mitochondrial oxygen consumption, and dysregulated TTFL factor expression patterns - CLOCK, CRY1, and CRY2 were upregulated while PER2 was downregulated in these cells ( Pacelli et al, 2019 ). Epigenetic modifications may also play a role in aberrant clock gene expressions.…”

Section: α-Synuclein Proteinopathiesmentioning

confidence: 99%

The Molecular Clock and Neurodegenerative Disease: A Stressful Time

Carter

Justin

Gulick

et al. 2021

Front. Mol. Biosci.

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Circadian rhythm dysfunction occurs in both common and rare neurodegenerative diseases. This dysfunction manifests as sleep cycle mistiming, alterations in body temperature rhythms, and an increase in symptomatology during the early evening hours known as Sundown Syndrome. Disruption of circadian rhythm homeostasis has also been implicated in the etiology of neurodegenerative disease. Indeed, individuals exposed to a shifting schedule of sleep and activity, such as health care workers, are at a higher risk. Thus, a bidirectional relationship exists between the circadian system and neurodegeneration. At the heart of this crosstalk is the molecular circadian clock, which functions to regulate circadian rhythm homeostasis. Over the past decade, this connection has become a focal point of investigation as the molecular clock offers an attractive target to combat both neurodegenerative disease pathogenesis and circadian rhythm dysfunction, and a pivotal role for neuroinflammation and stress has been established. This review summarizes the contributions of molecular clock dysfunction to neurodegenerative disease etiology, as well as the mechanisms by which neurodegenerative diseases affect the molecular clock.

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Section: α-Synuclein Proteinopathiesmentioning

confidence: 99%

The Molecular Clock and Neurodegenerative Disease: A Stressful Time

Carter

Justin

Gulick

et al. 2021

Front. Mol. Biosci.

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“…Along with this line of evidence, we showed in earlier studies that primary parkinmutant fibroblasts, carrying different mutations in the PARK2 gene, displayed severe ultrastructural abnormalities, mainly in mitochondria [4,24], altered expression of proteins involved in structural dynamics of cytoskeleton, oxidative stress response, Ca 2+ homeostasis, and RNA processing [25,26]. Furthermore, parkin-mutant fibroblasts showed an altered lipid profile [27], dysfunctions of lysosomal function [28] and of clock gene-dependent energy metabolism [29], and higher Ca 2+ and cAMP basal levels [4,5,30].…”

Section: Introductionmentioning

confidence: 53%

Resveratrol Treatment in Human Parkin-Mutant Fibroblasts Modulates cAMP and Calcium Homeostasis Regulating the Expression of Mitochondria-Associated Membranes Resident Proteins

et al. 2021

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Parkin plays an important role in ensuring efficient mitochondrial function and calcium homeostasis. Parkin-mutant human fibroblasts, with defective oxidative phosphorylation activity, showed high basal cAMP level likely ascribed to increased activity/expression of soluble adenylyl cyclase and/or low expression/activity of the phosphodiesterase isoform 4 and to a higher Ca2+ level. Overall, these findings support the existence, in parkin-mutant fibroblasts, of an abnormal Ca2+ and cAMP homeostasis in mitochondria. In our previous studies resveratrol treatment of parkin-mutant fibroblasts induced a partial rescue of mitochondrial functions associated with stimulation of the AMPK/SIRT1/PGC-1α pathway. In this study we provide additional evidence of the potential beneficial effects of resveratrol inducing an increase in the pre-existing high Ca2+ level and remodulation of the cAMP homeostasis in parkin-mutant fibroblasts. Consistently, we report in these fibroblasts higher expression of proteins implicated in the tethering of ER and mitochondrial contact sites along with their renormalization after resveratrol treatment. On this basis we hypothesize that resveratrol-mediated enhancement of the Ca2+ level, fine-tuned by the ER–mitochondria Ca2+ crosstalk, might modulate the pAMPK/AMPK pathway in parkin-mutant fibroblasts.

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“…For instance the regulation of endoplasmic reticulum-to-mitochondrial contacts by Parkin via Mfn-2 (Basso et al, 2018). Also, Pacelli et al (2019) reported altered severe damping of the bioenergetic oscillatory patterns associated to circadian rhythms and molecular clockworks in fibroblasts from PRKN-PD patients that may conditioning mitochondrial quality control and mitophagy. One study performing a whole-genome expression analysis by RNA-sequencing found that different PRKN mutations were associated with a large number of gene expression changes at the transcriptome level (González-Casacuberta et al, 2018).…”

Section: Molecular Mechanisms Underlying Pd Pathogenesis: Mitochondrimentioning

confidence: 98%

Bioenergetics and Autophagic Imbalance in Patients-Derived Cell Models of Parkinson Disease Supports Systemic Dysfunction in Neurodegeneration

et al. 2019

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Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder worldwide affecting 2–3% of the population over 65 years. This prevalence is expected to rise as life expectancy increases and diagnostic and therapeutic protocols improve. PD encompasses a multitude of clinical, genetic, and molecular forms of the disease. Even though the mechanistic of the events leading to neurodegeneration remain largely unknown, some molecular hallmarks have been repeatedly reported in most patients and models of the disease. Neuroinflammation, protein misfolding, disrupted endoplasmic reticulum-mitochondria crosstalk, mitochondrial dysfunction and consequent bioenergetic failure, oxidative stress and autophagy deregulation, are amongst the most commonly described. Supporting these findings, numerous familial forms of PD are caused by mutations in genes that are crucial for mitochondrial and autophagy proper functioning. For instance, late and early onset PD associated to mutations in Leucine-rich repeat kinase 2 (LRRK2) and Parkin (PRKN) genes, responsible for the most frequent dominant and recessive inherited forms of PD, respectively, have emerged as promising examples of disease due to their established role in commanding bioenergetic and autophagic balance. Concomitantly, the development of animal and cell models to investigate the etiology of the disease, potential biomarkers and therapeutic approaches are being explored. One of the emerging approaches in this context is the use of patient’s derived cells models, such as skin-derived fibroblasts that preserve the genetic background and some environmental cues of the patients. An increasing number of reports in these PD cell models postulate that deficient mitochondrial function and impaired autophagic flux may be determinant in PD accelerated nigral cell death in terms of limitation of cell energy supply and accumulation of obsolete and/or unfolded proteins or dysfunctional organelles. The reliance of neurons on mitochondrial oxidative metabolism and their post-mitotic nature, may explain their increased vulnerability to undergo degeneration upon mitochondrial challenges or autophagic insults. In this scenario, proper mitochondrial function and turnover through mitophagy, are gaining in strength as protective targets to prevent neurodegeneration, together with the use of patient-derived fibroblasts to further explore these events. These findings point out the presence of molecular damage beyond the central nervous system (CNS) and proffer patient-derived cell platforms to the clinical and scientific community, which enable the study of disease etiopathogenesis and therapeutic approaches focused on modifying the natural history of PD through, among others, the enhancement of mitochondrial function and autophagy.

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Parkin Mutation Affects Clock Gene-Dependent Energy Metabolism

Cited by 32 publications

References 82 publications

The Molecular Clock and Neurodegenerative Disease: A Stressful Time

The Molecular Clock and Neurodegenerative Disease: A Stressful Time

Resveratrol Treatment in Human Parkin-Mutant Fibroblasts Modulates cAMP and Calcium Homeostasis Regulating the Expression of Mitochondria-Associated Membranes Resident Proteins

Bioenergetics and Autophagic Imbalance in Patients-Derived Cell Models of Parkinson Disease Supports Systemic Dysfunction in Neurodegeneration

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